Alcohol abuse by human beings and animal models of alcohol consumption have been shown to be associated with suppression of innate and acquired immune responses, which increases susceptibility to and pathogenicity of infections. Among the more important infectious diseases associated with alcohol abuse are respiratory infections. Several groups have investigated bacterial infections of the lungs of experimental animals, but little information has been obtained regarding the effects of chronic alcohol consumption on pulmonary viral infections. We have established an animal model of chronic alcohol consumption and pulmonary viral infection. The preliminary data we have obtained support the suggestion that chronic alcohol consumption is associated with increased severity of infection. The following hypotheses are proposed on the basis of the preliminary data and will be tested in a well-established animal model of chronic (months) alcohol consumption with a virus model relevant to pulmonary infections of human beings. The overarching hypothesis is that chronic alcohol abuse results in increased susceptibility to and severity of respiratory viral infections. Specific hypotheses addressed in this exploratory/developmental grant application are the following: 1. Chronic alcohol consumption alters the early (innate) immune responses to a pulmonary viral infection to A. limit early control of viral infection by suppressing activation of natural killer cells, which limits production of interferon (IFN)-3. B. increase production of proinflammatory cytokines and chemokines. The continued viral infection would result in sustained production of these mediators, resulting in continued pulmonary inflammation. Further, failure to signal through the IFN receptor would limit the early control of the infection. 2. Chronic alcohol consumption suppresses the acquired immune response and biases to a T helper cell subtype 2 (TH2) type response to limit migration or activation (or both) of antigen-specific CD8+ T cells to clear infection in the lungs. A combination of these effects would inhibit clearance of the viral infection and, thus, increase the inflammatory response in the lungs, as well as possibly increase the chances of development of chronic lung disease, which would impair lung function. The data obtained from this exploratory grant application would provide the basis for a further mechanistic R01 application. Ultimately, this line of study would yield important information regarding the effects of alcohol abuse on the pathogenicity of pulmonary viral infections and, perhaps, potential interventions. One of the more important infectious diseases associated with alcohol abuse are respiratory infections, but there have been little information obtained regarding the effects of chronic alcohol consumption on pulmonary viral infections. Because of the suppression of the immune response associated with alcohol abuse and alcohol-associated changes in the lung, it is reasonable to suggest increased susceptibility to respiratory viral infections. [unreadable] [unreadable] [unreadable]